Influenza virus causes annual epidemics and periodic pandemics, resulting in the loss of millions of human lives, and is recognized as an important public heath priority of the U.S. Due to the high mutation rate of influenza virus, widespread resistance to anti-viral drugs targeting viral proteins and vaccines constitutes a major challenge for therapeutic intervention. Because all viruses utilize host factors and machinery to complete their life cycle, targeting host factors that regulate virus replication may provide a solution to mutagenesis- associated viral escape. However, relatively less is known about the host factors that are involved in mediating influenza virus replication compared to viral proteins. Therefore, the long-term goal of this project is to understand the molecular mechanisms of host factors that regulate influenza virus replication and develop anti- viral drugs targeting these host factors. MicroRNAs are small non-coding RNAs that control the expression of the majority of genes at the post-transcriptional level and are implicated in diverse biological processes and diseases, including viral infections. Our understanding of the role of host cellular microRNAs in influenza virus replication is very limited. The overall objective of the current application is to investigae the functional role of the host miR-193b in influenza virus replication. We will test the hypothesi that miR-193b attenuates influenza virus replication by inhibiting LEF1-mediated Wnt/?-catenin signaling. Aim I will delineate the mechanisms of miR-193b-mediated repression of influenza virus replication. Aim II will evaluate the in vivo therapeutic efficacy of miR-193b against influenza virus infection. We expect to establish a previously unrecognized role for miR- 193b-mediated regulation of the Wnt/?-catenin signaling pathway in influenza virus replication.